Modulation and molecular mechanisms of GPR56 function

GPR56功能的调节和分子机制

基本信息

  • 批准号:
    9110022
  • 负责人:
  • 金额:
    $ 4.86万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-07-01 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The overall goal of my project is to engineer proteins that perturb and thereby elucidate the molecular mechanisms by which adhesion G protein-coupled receptors (aGPCRs) function. Members of the superfamily of cell-surface signaling proteins known as G protein-coupled receptors (GPCRs) have been validated as successful drug targets. aGPCRs make up the second largest GPCR family and have recently been implicated in a variety of diseases, including neurological disorders, and many types of cancer. Characterized by their large and diverse extracellular regions (ECRs), aGPCRs play a role in cell adhesion. Due to the importance of aGPCRs in disease, as well as the proven druggability of GPCRs, aGPCRs are an unexplored, yet potentially impactful class of drug targets. To this end, before drug development can begin, it is imperative to systematically define the feasibility of targeting aGPCRs with drugs. One of the best-studied aGPCRs, GPR56, has been linked to the progression of many cancers as well as brain development, including its role in the developmental brain disorder bilateral frontoparietal polymicrogyria. Though two GPR56 ligands have been identified, the molecular mechanisms by which GPR56 functions remain unclear. Key to my project is the synergistic implementation of GPR56 fragment purification, cutting-edge protein engineering, X-ray crystallography, and cell signaling assays. Using these techniques, I will systematically elucidate the molecular mechanisms that govern the biological functions of GPR56 and thereby assess its durggability. My proposal consists of three aims, the first of which is to engineer binding proteins, termed monobodies (Mbs), that specifically bind GPR56 with high affinity. Using purified GPR56 fragments as targets for phage display library selection, I have engineered a Mb that binds the ECR of GPR56 with high affinity and specificity. Using the techniques I have already successfully employed, I will engineer Mbs that bind other sites on GPR56. Second, I will determine the regions of GPR56 that interact with natural and engineered proteins. I have solved the crystal structure of my Mb bound to the ECR of GPR56. This is the first structure of the full ECR of any aGPCR and also the first structure of an aGPCR fragment in complex with a binding partner. I will crystallize soluble fragments of GPR56 in complex with new Mbs in order to precisely map their binding sites. I will also purify tissue transglutaminase 2, a ligand of GPR56, and attempt to solve its structure bound to GPR56. Third, I will characterize the biological roles of distinct regions of GPR56. By establishing GPR56 signaling assays in my lab, I will assess the functional implications of Mb binding and structure-guided GPR56 mutations in parallel. With the ultimate goal of combatting aGPCR-mediated diseases, it is crucial to gain a clear and accurate understanding of the mechanisms that govern GPR56 function such that the feasibility of drugging this important aGPCR can be evaluated.
 描述(由申请人提供):我的项目的总体目标是工程蛋白质,干扰,从而阐明粘附G蛋白偶联受体(aGPCR)功能的分子机制。被称为G蛋白偶联受体(GPCR)的细胞表面信号蛋白超家族成员已被证实为成功的药物靶点。aGPCR构成了第二大GPCR家族,并且最近已经涉及多种疾病,包括神经障碍和许多类型的癌症。aGPCR以其大而多样的细胞外区域(ECR)为特征,在细胞粘附中起作用。由于aGPCR在疾病中的重要性,以及GPCR已被证明的可药用性,aGPCR是一种未被探索的,但潜在有影响力的一类药物靶标。为此,在药物开发开始之前,必须系统地定义用药物靶向aGPCR的可行性。研究得最好的aGPCR之一GPR56与许多癌症的进展以及大脑发育有关,包括其在发育性大脑疾病双侧额顶叶多微回症中的作用。虽然已经鉴定了两种GPR56配体,但GPR56功能的分子机制仍不清楚。我的项目的关键是GPR56片段纯化,尖端蛋白质工程,X射线晶体学和细胞信号分析的协同实施。利用这些技术,我将系统地阐明GPR56的生物学功能的分子机制,从而评估其耐受性。我的建议包括三个目标,其中第一个是工程结合蛋白,称为单体(Mbs),特异性结合GPR56具有高亲和力。使用纯化的GPR56片段作为噬菌体展示文库选择的靶标,我已经设计了一种Mb,其以高亲和力和特异性结合GPR56的ECR。使用我已经成功使用的技术,我将设计绑定GPR56上其他站点的MBS。其次,我将确定GPR56与天然和工程蛋白相互作用的区域。我已经解决了与GPR 56的ECR结合的Mb的晶体结构。这是任何aGPCR的完整ECR的第一个结构,也是与结合配偶体复合的aGPCR片段的第一个结构。我将使GPR56的可溶性片段与新的Mb复合结晶,以精确地绘制它们的结合位点。我还将纯化组织转氨酶2,GPR56的配体,并试图解决其结构结合GPR56。第三,我将描述GPR56不同区域的生物学作用。通过在我的实验室建立GPR56信号传导测定,我将平行评估Mb结合和结构引导的GPR56突变的功能意义。为了对抗aGPCR介导的疾病的最终目标,至关重要的是要清楚和准确地了解控制GPR56功能的机制,以便评估这种重要的aGPCR药物的可行性。

项目成果

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Gabriel Salzman其他文献

Gabriel Salzman的其他文献

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{{ truncateString('Gabriel Salzman', 18)}}的其他基金

Modulation and molecular mechanisms of GPR56 function
GPR56功能的调节和分子机制
  • 批准号:
    9300929
  • 财政年份:
    2015
  • 资助金额:
    $ 4.86万
  • 项目类别:

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